KR910002882A - Phosphorus-containing squalene synthetase inhibitors and preparation methods thereof - Google Patents

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Phosphorus-containing squalene synthetase inhibitors and preparation methods thereof

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Claims (74)

A compound having the following structural formula and all stereoisomers thereof, Wherein m is 1,2 or 3, n is 0,1,2 or 3, Y ¹ and Y ² are H or halogen, R ² , R ³ and R ⁴ are the same or different and each is H, Alkyl of the metal ions C ₁ to C ₈ or C ₃ to C ₁₂ is alkenyl, X is O, S, NH, —NCH ₂ R ¹⁵ , wherein R ¹⁵ is H or C ₁ to C ₅ alkyl And R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are the same or different, respectively Or is a single bond, provided that when Q ¹ is a bond Q ² and Q ³ are a bond, and when Q ² is a bond Q ³ is a bond, wherein R ⁶ is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or lower alkylthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, R ⁵ is Or CH ₃ (CH ₂ ) P— wherein P is an integer from 2 to 7, R ¹⁰ and R ¹¹ are the same or different and are hydrogen, lower alkyl, haloalkyne, halogen or lower alkenyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) s where s is an integer from 2 to 7, R ¹² is hydrogen, lower alkyl, halogen or lower alkenyl, and R ¹³ and R ¹⁴ are the same or different And each lower alkyl, R ¹⁶ is H or lower alkyl, P is an integer of 2 to 7, provided that when Q ¹ , Q ² and Q ³ are all bonds, R ¹⁰ and R ¹¹ may be H. And R ⁵ cannot be CH ₃ (CH ₂ ) p − (where P ≦ 4). 2. A compound according to claim 1 wherein X is zero. ^2. A compound according to claim 1, wherein Y ¹ and Y ² are each F. 2. The compound of claim 1, wherein Y ¹ and Y ² are each H. ³ . 2. A compound according to claim 1, wherein m is 1 or 2 and n is 0 or 1. The compound of claim 1, wherein R ¹ is R ⁵ -Q ¹ -Q ² , wherein Q ¹ , and Q ² are groups excluding a single bond. The compound of claim 5, wherein R ⁵ is Q ¹ is Q ² is the same as or different from Q ¹ And Q ³ is a bond. The compound of claim 6, wherein X is 0 or NH. 7. A compound according to claim 6, wherein X is 0, n is 0, m is 1, and Y ¹ and Y ² are H. The compound of claim 1, wherein R ⁵ is Q ¹ is And Q ³ is a bond. The compound of claim 1, wherein R ⁵ is CH ₃ (CH ₂ ) p − and Q ¹ is Q ² is the same as or different from Q ¹ And Q ³ is a bond. The compound of claim 1, wherein R ⁵ is Q ¹ is Q ² is the same as or different from Q ¹ And Q ³ is a bond. The compound of claim 1, wherein at least ^one of R ² , R ³ , and R ¹ is an alkali metal salt or an alkyl earth metal salt. 2. The compound of claim 1, wherein R ² , R ³ , and R ⁴ are each H. ³ . The compound of claim 1, wherein at least one of R ² , R ³ , and R ⁴ is lower alkyl or lower alkenyl. The compound according to claim 1, wherein (E, E)-[[1-methylethoxy [[(3,7,11-trimethyl-2,6,10-dodecartrienyl) oxy] methyl] phosphinyl] methyl Phosphonic acid, dimethyl ester. (E, E)-[[hydroxy [[(3,7,11-trimethyl-2,6,10-dodecattrienyl) oxy] methyl] phosphinyl] methyl] phosphonic acid, Or a tripotassium salt or trisodium salt thereof. (E, E)-[[methoxy [[(3,7,11-trimethyl-2,6,10-dodecatrienyl) oxy] methyl] phosphinyl] methyl] phosphonic acid, Compounds that are dimethyl esters. The compound according to claim 1, which is (E)-[[[[(3,7-dimethyl-2,5-octadienyl) oxy] methyl] ethoxy phosphinyl] methyl] phosphonic acid, dimethyl ester. The compound according to claim 1, which is (E)-[[[[(3,7-dimethyl-2,6-octadienyl) oxy] methyl] hydroxy phosphinyl] methyl] phosphonic acid, or a trisodium salt thereof. . The compound according to claim 1, which is (E, E)-[[ethoxy [[(4,8,12-trimethyl-3,7,11-tridecatrienyl) oxy] methyl] -phosphonic acid, dimethyl ester compound. (E, E)-[[hydroxy [[(4,8,12-trimethyl-3,7,11-tridecatrienyl) oxy] methyl] phosphinyl] methyl] phosphonic acid according to claim 1 Or a tripotassium salt thereof. (E, E)-[[hydroxy [[(3,7,11-trimethyl-2,6,10-dodecattrienyl) oxy] methyl] phosphinyl] methyl] phosphonic acid, Monomethyl ester, dipotassium salt. (E, E)-[[ethoxy [[(5,9,13-trimethyl-4,8,12-tetradecatriethyl) oxy] methyl] phosphinyl] methyl] phosphonic acid, Compounds that are dimethyl esters. (E, E)-[[hydroxy [[(5,9,13-trimethyl-4,8,12-tetradecatriethyl) oxy] methyl] phosphinyl] methyl] phosphonic acid, Or a trisodium salt thereof. (E, E)-[[hydroxy [[(3,7,11-trimethyl-2,6,10-dodecattrienyl) oxy] methyl] phosphinyl] methyl] phosphonic acid, Or a disodium thereof. (E, E)-[[ethoxy [2-[(3,7,11-trimethyl-2,6,10-dodecattrienyl) oxy] ethyl] phosphinyl] methyl] force according to claim 1 Phenolic acid, dimethyl ester. (E, E)-[[hydroxy [2- (3,7,11-trimethyl-2,6,10-dodecatrienyl) oxy] ethyl] phosphinyl] methyl] phosphonic acid Or a trisodium salt thereof. (E, E)-[[[((7,11-dimethyl-6,10-dodecadiene-2-ynyl) oxy] methyl] (1-methylethoxy) phosphinyl] methyl according to claim 1 Phosphonic acid, dimethyl ester. (E, E)-[[[[(7,11-dimethyl-6,10-dodecadiene-2-ynyl) oxy] methyl] hydroxyphosphinyl] methyl] phosphonic acid, or Its trisodium salt. (E, E)-[[[((3,7-dimethyl-2,6-dodecadienyl) oxy] methyl] (1-methylethoxy) phosphinyl] methyl] phosphonic acid according to claim 1 And dimethyl ester. (E, E)-[[[[(3,7-dimethyl-2,6-dodecadienyl) oxy] methyl] hydroxyphosphinyl] methyl] phosphonic acid, or trisodium thereof according to claim 1 Salts. (E, E)-[[(1-methylethoxy [(3,7,11-trimethyl-2,6-dodecadienyl) oxy] methyl] phosphinyl] methyl] phosphonic acid And dimethyl ester. The method according to claim 1, wherein (E, E)-[[hydroxy [[(3,7,11-trimethyl-2,6-dodecadienyl) oxy] methyl] phosphinyl] methyl] phosphonic acid, or Trisodium salt. The compound according to claim 1, wherein (E, E)-[[methoxy [((3,7,11-trimethyl-2,6,10-dodecattrienyl) oxy] methyl] phosphinyl] difluoromethyl] Phosphonic acid, diethyl ester. The compound according to claim 1, wherein (E, E)-[[hydroxy] [(3,7,11-trimethyl-2,6,10-dodecattrienyl) oxy] methyl] phosphinyl] difluoromethyl] Phosphonic acid, monoethyl ester trisodium salt. The compound according to claim 1, wherein (E, E)-[[hydroxy] [(3,7,11-trimethyl-2,6,10-dodecattrienyl) oxy] methyl] phosphinyl] difluoromethyl] Phosphonic acid, or a trisodium salt thereof. (E, E)-[[([(7,11-dimethyl-2,6,10-dodecatenyl) oxy] methyl] (1-methylethoxy) phosphinyl] methyl] Phosphonic acid, dimethyl ester. The method according to claim 1, wherein (E, E)-[[[[(7,11-dimethyl-2,6,10-dodecatenyl) oxy] methyl] hydroxyphosphinyl] methyl] phosphonic acid, or Trisodium salt. (E, E)-[[[[(3-chloro-7,11-dimethyl-2,6,10-dodecatrienyl) oxy] methyl] ethoxyphosphinyl] methyl] force according to claim 1 Phenolic acid, dimethyl ester. (E, E)-[[[((3-chloro-7,11-dimethyl-2,6,10-dodecatenyl) oxy] methyl] hydroxy phosphinyl] methyl] force according to claim 1 Phenolic acid, or trisodium salt thereof. (E, E)-[[ethoxy [[(3,7,11-trimethyl-2,6,10-dodecatrienyl) thio] methyl] phosphinyl] methyl] phosphonic acid, Compounds that are dimethyl esters. (E, E)-[[hydroxy [[(3,7,11-trimethyl-2,6,10-dodecatrienyl) thio] methyl] phosphinyl] methyl] phosphonic acid, Or a trisodium salt thereof. (E, E)-[[[[(3-ethyl-7,11-dimethyl-2,6,10-dodecatenyl) oxy] methyl] (1-methylethoxy)- Phosphinyl] methyl] phosphonic acid and dimethyl ester. (E, E)-[[[[(3-ethyl-7,11-dimethyl-2,6,10-dodecatenyl) oxy] methyl] hydroxyphosphinyl] methyl] force according to claim 1 Compounds that are phonic acid, or trisodium salt. (2Z, 6E)-[[[(3-ethyl-7,10-dimethyl-2,6,10-dodecatrienyl) oxy] methyl] (1-methylethoxy)- Phosphinyl] methyl] phosphonic acid and dimethyl ester. (2Z, 6E)-[[[[(3-ethyl-7,10-dimethyl-2,6,10-dodecaryrienyl) oxy] methyl] hydroxyphosphinyl] methyl] force according to claim 1 Compounds that are phonic acid, or trisodium salt. (E)-[[([(8,12-dimethyl-7,11-tridecadiene-3-ynyl) oxy] methyl] (1-methylethyl) phosphinyl] phosphinylmethyl] Phosphonic acid, dimethyl ester. (E)-[[[((8,12-dimethyl-7,11-tridecadiene-3-ynyl) oxy] methyl] hydroxyphosphinyl] methyl] phosphonic acid, or three thereof Compound that is sodium. Use of the compound of claim 1 for inhibiting or treating hypercholesterolemia. Use of the compound of claim 1 for inhibiting or treating atherosclerosis. A low cholesterol or hypolipidemic composition comprising the compound of claim 1 as an active ingredient and a pharmaceutically acceptable carrier. Use of the compound of claim 1 to inhibit cholesterol biosynthesis. A compound having the structure Wherein n is 0, 1, 2 or 3, m is 1, 2 or 3, X ¹ is 0, S or N-Pro, where Pro is a nitrogen protecting group, X ² is 0 or S, R ²ⁿ is C ₁ -C ₈ alkyl or C ₃ -C ₁₂ alkenyl, R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are each , , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is a bond, and R ⁸ is H, lower alkyl halo or haloalkyl, R <SB <7H, halogen, lower alkyl or alkylthio, R ₈ is H, halogen trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, R ⁵ is , R ¹⁶ -C≡C-CH ₂ -or CH ₃ (CH ₂ ) P-, wherein P is 2 to 7 and R ¹⁰ and R ¹¹ are each hydrogen, lower alkyl, halogen, lower alkenyl or haloalkyl Or R ¹⁰ and R ¹¹ together form (CH ₂ ) S where S is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen or lower alkenyl, and R ¹³ and R ¹⁴ are Each lower alkyl, R ¹⁶ is lower alkyl or H, provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ , R ¹¹ cannot be H and R ⁵ is CH ₃ (CH ₂ ) p- (where P≤4) cannot be obtained. 55. The compound of claim 54, having the structural formula: Wherein m, n, R ¹ , X ¹ and R ^2a are as defined in claim 54. 55. The compound of claim 54, wherein X ¹ is NH or N-Pro. 55. The compound of claim 54, having the structural formula: Wherein m, n, R ¹ , X ¹ and R ^2a are as defined in claim 54. 55. The compound of claim 54, having the structural formula: Wherein m, n, R ¹ , X ¹ and R ^2a are as defined in claim 54. 55. The compound of claim 54, having the structural formula: Wherein m, n, R ¹ , X ¹ and R ^2a are as defined in claim 54. [[[[(Trifluoromethyl) sulfonyl] oxy] methyl] phosphonic acid, bis (1-methylethyl ester). A process for producing a compound of formula (I), wherein the diester of general formula (IA) is treated with a water-soluble strong base, an alkali metal cyanide or an alkaline earth metal halide. In each formula, n is 0, 1, 2 or 3, m is 1, 2 or 3, X ¹ is 0, S or N-Pro, where Pro is a nitrogen protecting group and R ²ⁿ is C ₁ -C ₈ Alkyl or C ₃ -C ₁₂ alkenyl, R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are each , -CH ₂ -C≡C-CH ₂ - or or a bond, however, wherein Q ² and Q ³ may be combined if Q ¹ is a bond, when Q ² is bonded Q ³ is a bond, in which R ⁶ Is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or alkylthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁸ is H or lower alkyl, R ⁵ is , R ¹⁶ -C≡C-CH ₂ -or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are the same or different from each other and are hydrogen, lower alkyl, halogen, lower Alkenyl or haloalkyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) S, wherein S is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen, or lower alkenyl, R ¹³ and R ¹⁴ are each lower alkyl, R ¹⁶ is lower alkyl or H], provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ , R ¹¹ cannot be H, and R is ⁵ cannot be CH ₂ (CH ₂ ) p − (where P ≦ 4). The diester of the following general formula (IIA) was treated with bromotrimethylsilane or iodinetrimethylsilane in the presence of 2, 4, 6-collidine in an inert atmosphere, followed by dicyclohexylcarbodii of alcohol of general formula R ^2a OH. The monoester manufacturing method of the following general formula (II) characterized by processing with mid and forming monoester. In each formula, n is 0, 1, 2 or 3, m is 1, 2 or 3, X ¹ is 0 or S, X ² is 0 or S, R ²ⁿ is C ₁ -C ₈ alkyl or C ₃ -C ₁₂ alkenyl, R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are each , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is a bond and Q ⁶ is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or alkylthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, R ⁵ Is , R ¹⁶ -C≡C-CH ₂ -or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are the same or different from each other and are hydrogen, lower alkyl, halogen, lower Alkenyl haloalkyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) S, wherein S is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen or lower alkenyl, and R ¹³ And R ¹⁴ are each lower alkyl, and R ¹⁶ is lower alkyl or H], provided that when Q ¹ , Q ² and Q ³ are all bonded, R ¹⁰ , R ¹¹ may not be H, and R ⁵ is Cannot be CH ₃ (CH ₂ ) p − (p 4). The monoester of the following general formula (IIA) was treated with N, N-diethyl (trimethylsilyl) amine under an inert atmosphere, and the obtained reaction product was treated with oxalyl chloride to form an acid chloride. A process for producing a compound of the general formula (III) below, characterized by treating with a metal salt of -1) to form phosphinyl phosphonate of the general formula (III). In each formula, n is 1, 2 or 3, n is 0, 1, 2 or 3, Y ¹ , and Y ² are H or halogen, R ^2a , R ^3a and R ^4a are the same as or different from each other. , C ₁ to C ₈ alkyl or to C ₁₂ alkenyl, X is 0 or S, and R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ is each , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is necessarily a bond, Q ⁶ Is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or alkylthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, R ⁵ is , , R ¹⁶ -C≡C-CH ₂ -or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are the same or different from each other and are hydrogen, lower alkyl, halogen, lower Alkenyl haloalkyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) S, wherein S is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen, or lower alkenyl, R ¹³ and R ¹⁴ are each lower alkyl, R ¹⁶ is lower alkyl or H] provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ , R ¹¹ may not be H, and R ⁵ Cannot be CH ₃ (CH ₂ ) p − (p ≦ 4) and M is Li ⁺ , Na ^+, K ⁺ , ⁺ MgHal, ⁺ ZnHal, ⁺ CE (Hal) ₂ or Cu ⁺ . Treatment of the phosphinyl phosphonate of the general formula (IV) with a dealkylating agent, followed by treatment with a strong inorganic base to form a salt of the general formula (JVA-1), and treatment of this salt with a strong acid to A process for producing the following general formula (IVB) compound, characterized by forming an acid. Wherein m is 1, 2 or 3, n is 0, 1, 2 or 3, Y ¹ , Y ² is H or halogen, and R ^2a , R ^3a and R ^4a are each of C ₁ -C ₈ Alkyl or C ₃ -C ₁₂ alkenyl, X is 0 or S, R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are each , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is necessarily a bond, Q ⁶ is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H, or lower alkyl, R ⁵ is , R ¹⁶ -C≡C-CH- or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are the same or different from each other and are hydrogen, lower alkyl, halogen, lower egg, respectively Is kenyl haloalkyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) S, wherein S is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen, or lower alkenyl, and R ¹³ And R ¹⁴ are each lower alkyl, R ¹⁶ is lower alkyl or H], provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ , R ¹¹ cannot be H and R ⁵ is Cannot be CH ₃ (CH ₂ ) p- (where p ≦ 4) and R ² , R ³ and R ⁴ are the same or different from each other and are each H, metal ion, C ₁ -C ₈ alkyl or C ₃ -C ₁₂ alkenyl. The monoester solution of the following general formula (VA) in pyridine was treated with p-nitrophenol, 4-dimethylaminopyridine and dicyclohexylcarbodiimide under inert atmosphere to form nitrophenyl ester of the following general formula (VB), The nitrophenyl ester is treated with a metal salt of the following structural formula (VC) to form phosphinyl phosphonate of the following general formula (V), wherein the compound of formula (V) is prepared. In each of the above formula, m is 1, 2 or 3, n is 0, 1, 2 or 3, Y ¹ , Y ² is H or halogen, and R ^2a , R ^3a and R ^4a are each independently C ₁ -C Alkyl of ₈ or alkenyl of C ₃ -C ₁₂ , X is 0 or S or N-Pro, R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ is each , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is necessarily a bond, Q ⁶ is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or alkalthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, R ⁵ is , R ¹⁶ -C≡C-CH- or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are the same or different from each other and are hydrogen, lower alkyl, halogen, lower egg, respectively alkenyl, and haloalkyl, or, or R ¹⁰ and R ¹¹ are together (CH ₂₎ S (here, S is 2 to 7 being) formed, and, R ¹² is hydrogen, lower alkyl, halogen or lower alkenyl, and R ¹³ R ¹⁴ is each lower alkyl, R ¹⁶ is lower alkyl or H] provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ and R ¹¹ may not be H and R ⁵ is CH ₃ (CH ₂ ) p −, where p ≦ 4, and M is Li ⁺ , Na ^+, K ⁺ , ⁺ MgHal, ⁺ Zn Hal, ⁺ Ce (Hal) _2, or Cu ⁺ . A process for producing a compound of formula (VI), characterized in that phosphinyl phosphonoate of formula (VIA) is treated with a dealkylating agent, followed by a strong organic base. Wherein m is 1, 2 or 3, n is 0, 1, 2 or 3, Y ¹ , Y ² is H or halogen, R ² , R ³ and R ⁴ are metal ions, X is NH R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are respectively , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is necessarily a bond, Q ⁶ is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or alkalthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, , R ¹⁶ -C≡C-CH- or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are the same or different from each other and are hydrogen, lower alkyl, halogen, lower egg, respectively Is kenyl or alkenyl haloalkyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) S, wherein S is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen or lower alkenyl, R ¹³ and R ¹⁴ are each lower alkyl, R ¹⁶ is lower alkyl or H], provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ , R ¹¹ cannot be H, and R is ⁵ cannot be CH ₃ (CH ₂ ) p-(p ≦ 4), and R ^2a , R ^3a and R ^4a are each independently of each other C ₁ -C ₈ alkyl or C ₃ -C ₁₂ alkenyl . A compound of formula (VII), wherein a solution of a compound of formula (VIIA) is treated with a compound of formula (VIIB), followed by a diazophosphonate of formula (VIIC). Method of preparation. In each formula, n is 1, 2 or 3 and m is 0, 1, 2 or 3, X ¹ is 0, S or N-Pro, where Pro is a nitrogen protecting group and R ²ⁿ is C ₁ -C ₈ alkyl Or C ₃ -C ₁₂ alkenyl, R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are each , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is necessarily a bond, Q ⁶ is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or alkalthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, , R ¹⁶ -C≡C-CH ₂ -or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are each hydrogen, lower alkyl, halogen, or haloalkyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) S where s is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen or lower alkenyl, and R ¹³ and R ¹⁴ are each lower alkyl R ¹⁶ is lower alkyl or H, provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ and R ¹¹ cannot be H and R ⁵ is CH ₃ (CH ₂ ) p. -(P≤4) The compound of formula (VII) is treated with a base under an inert atmosphere, followed by phosphonate of formula (VIIB) to form a diester of formula (VII). The manufacturing method of the diester of (5). In each formula, n is 0, 1, 2 or 3, m is 0, 1, 2 or 3, X ¹ is 0, S or NH, R ^2a is C ₁ -C ₈ alkyl or C ₃ -C ₁₂ Alkenyl and R ¹ is R ⁵ -Q ¹ -Q ² -Q ³ , wherein Q ¹ , Q ² and Q ³ are each , -CH ₂ -C≡C-CH ₂ -or a bond, provided that when Q ¹ is a bond, Q ² and Q ³ are necessarily bonds, and when Q ² is a bond, Q ³ is necessarily a bond, Q ⁶ is H, lower alkyl, halo or haloalkyl, R ⁷ is H, halogen, lower alkyl or alkalthio, R ⁸ is H, halogen, trimethylsilyl or lower alkyl, R ⁹ is H or lower alkyl, R ⁵ is , R ¹⁶ -C≡C-CH ₂ -or CH ₃ (CH ₂ ) p-wherein p is 2 to 7 and R ¹⁰ and R ¹¹ are each hydrogen, lower alkyl, halogen, or haloalkyl, or R ¹⁰ and R ¹¹ together form (CH ₂ ) S where s is 2 to 7, R ¹² is hydrogen, lower alkyl, halogen or lower alkenyl, and R ¹³ and R ¹⁴ are each lower alkyl R ¹⁶ is lower alkyl or H], provided that when Q ¹ , Q ² and Q ³ are all a bond, R ¹⁰ and R ¹¹ cannot be H and R ⁵ is CH ₃ (CH ₂ ) p. (Where p ≦ 4) and Z is P—CH ₃ C ₆ H ₄ SO ₃ — or CF ₃ SO ₃ —. m and R <^2a> are the same as what was defined by the said General formula (5). 69. The method of claim 68, wherein the base is n-butyllithium, sodium hydride or ((CH ₃ ) ₃ -Si ₂ ) ₂ NLi and the reaction is carried out in a temperature range of about -78 ° C to about 25 ° C and X ¹ is 0 or S, characterized in that the manufacturing method. 69. The method of claim 68, wherein the base is trialkylamine, the reaction is carried out in the temperature range of about -20 ° C to about 80 ° C, and X is NH. A complex formulation containing the compound of claim 1 and a therapeutic agent for hyperlipoproteinosis. 72. The method of claim 71, wherein the hyperlipoproteinemia therapeutic agent is probucol, gelfibrozil, bile acid scavenger, clofibrate, nicotinic acid, neomycin, P-aminosalicylic acid, benzafibrate, or HNG CoA reductase inhibitor. Complex formulation. 73. The combination formulation of claim 72, wherein the bile acid scavenger is cholestyramine, colesripol, or polydexide. 73. The combination formulation of claim 72, wherein the HMG, CoA reductase inhibitor is lovastatin, pravastatin or simvastatin. ※ Note: The disclosure is based on the initial application.